Aminophenylamidines, their production and their pharmaceutical use

ABSTRACT

The present invention relates to new aminophenylamidines, to processes for their production, and to their pharmaceutical use. These new compounds are useful as paraciticides, especially as anthelmintics. Some acylaminophenylformamidines, such as N-(p-acetamidophenyl)N&#39;&#39;,N&#39;&#39;-dimethylformamidine (U.S. Pat. No. 3,184,482) and N-phenylacetamidines, such as N-(p-chlorophenyl)-N&#39;&#39;,N&#39;&#39;dimethylacetamidine, are already known. These compounds are however inactive against the helminths mentioned below.

0 United States Patent 1 1 [111 3,911,010

Wollweber et al. 1 1 Oct. 7, 1975 l AMINOPHENYLAMIDINES, THEIR [51] Int. Cl. C07B 103/10 PRODUCTION AND THEIR [58] Field of Search 1. 260/562 R, 562 A, 562 B, PHARMACEUTICAL use 260/564 R [75] lnventors: Hartmund Wollweber,

Wuppertal-Elberfeld, Germany; [56] References Cned Winfried Flucke, Beenleigh, UNITED STATES PATENTS Austrahu 3.769274 10/1973 Wollweber et al 260/239 BF {73] Assignee: Bayer Aktiengesellschafl, Germany Filed: m 973 Primary Examiner-C. Davis [21] Appl. No: 398,692 [57] ABSTRACT Relaled Application Data The present invention relates to new aminophenylami- [62] Division of Ser. No. 151,581, June 9. 1971, Pat. No. dines, to processes for their production, and to their l pharmaceutical use These new compounds are useful as paraciticides, especially as anthelminticsl no] Forugn Apphcauon Pnonty Data Some acylaminophenylformamidines such as June 13, 1970 Germany 2029298 N (p acetamidophenyl) N"Ngdimehylformamidine (U.S. Pat. No. 3,184,482) and N-phenyl-acetamidines, [52] US. Cl. 260/562 H; 260/240 A; 260/243 A; Such as 260/2564 R; 260/287 R; 260/294.9; 260/302 R; 260/310 R; 260/345.7; 260/465 D; 260/556 R; 260/556 AR; 260/558 H; 260/559 H; 260/562 A; 260/562 B; 260/564 R N-(p-chlorophenyl)-N,N dimethylacetamidine, are already known. These compounds are however inactive against the helminths mentioned below.

6 Claims, N0 Drawings AMINOPHENYLAMIDINES, THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE This is a division of application Scr. No. l ,58] filed June 9, 197i, now US. Pat. No. 3,818.070.

This invention provides aminophenylamidines of the general formula:

R: R 9 R R4 s l N -N=('N I I H R" in which R is a straight or branched-chain alkyl, alkenyl or alkoxy group;

R is a COR group or an SO R group [in which R is a hydrogen atom; a straightor branchedchain alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy. alkoxyalkyloxy or alkoxyalkyl group; a cycloalkyl group or a cycloalkenyl group containing one or two double bonds, which cycloalkyl and cycloalkenyl groups can be substituted by one or more alkyl groups; a cycloalkylalkyl, benzocycloalkylalkyl, tetrahydrofuryl, tetrahydrofurfuryl or tetrahydropyranyl group which can be substitutetl by one or more alkyl groups; a trifluoromethyl group; an alkyl group substituted by one or more halogen atoms or by one or more cyano, hydroxy, acyloxy, alkoxy or oxo-groups; a carbalkoxyalkyl group; a cycloalkyl-alkoxy group; a cycloalkoxyor tetrahydrofurylalkoxy group; a phenylalkoxy, phenoxyalkoxy, phenoxy, phenylalkyl, phenyl, phenylalkcnyl or naphthyl group, in which the aromatic ring can be substituted by one or more alkyl, alkenyl, alkoxy, hydroxy, acyloxy, nitro, trifluoromethyl, cyano, carbethoxy, alkylsulphonyl, acylamino or alkylsulphonyl-amino groups or fluorine, chlorine or bromine atoms; a heteroaromatic ring system which can be substituted by one or more alkyl groups; a furylalkyl, thienylalkyl, indolylalkyl, furylalkoxy or thienylalkoxy, group which can be substituted by one or more alkyl groups; or a phenylalkyl group, the alkyl part of which is substituted by a hydroxy, acyloxy, or alkoxy group; and

R is a straightor branched-chain alkyl or alkenyl group, an aralkyl group, a cycloalkyl group, or a cycloalkyl-alkyl group;]

R, R" and R' can be the same or different and is each a hydrogen or halogen atom or a straightor branched-chain alkyl, alkenyl or alkoxy group or a cyano or trifluoromethyl group;

R is a straightor branched-chain alkyl, alkenyl, al-

kynyl or alkoxy group; and

R is a straightor branched-chain alkyl or alkcnyl group of a cyclo-alkyl group;

and their salts.

These compounds are useful for combating parasites,

especially hclminths.

The alkyl groups R as well as the alkyl part of the alkoxy groups R. preferably contain l to 5. especially l or 2, carbon atoms, and the alkenyl group R preferably contains 2 to 5 carbon atoms.

The cycloalkyl group R preferably contains 3 to 7, more preferably 5 to 7, carbon atoms.

The alkyl groups, and the alkyl component ofthe alkoxy groups R, R" and R" preferably contain l to 4, especially l or 2, carbon atoms. The alkenyl groups R", R and R preferably contain 2 to 4 carbon atoms.

Halogens R", R" and R are generally fluorine, chlorine and bromine, but preferably chlorine.

Alkyl radicals. as well the alkyl constituents of the alkoxy groups R, preferably contain l to 4, especially l or 2, carbon atoms. Alkenyl and alkynyl radicals R preferably contain 2 to 4 carbon atoms.

Alkyl groups R preferably contain 1 to 5, especially 1 or 2, carbon atoms, and alkenyl groups R preferably contain 2 to 5 carbon atoms.

The alkyl groups, and the alkyl component of the alkoxy groups R, preferably contain 1 to 6, especially 1 to 3, carbon atoms. The alkenyl and alkynyl groups R, and the allkenyl and alkynyl components of the alkenyloxy and alkynyloxy groups R, preferably contain 2 to 6, especially 2 or 3, carbon atoms. Alkoxyalkyloxy and alkoxyalkyl groups R preferably each contain 2 to 6, preferably 2 or 3, carbon atoms. Cycloalkyl groups R' contain 3 to 7, preferably 3 to 6, carbon atoms. The cycloalkyl groups R can contain one or more, preferably one, alkyl group having preferably 1 to 4, especially l or 2, carbon atoms.

The cycloalkylalkyl groups R generally contains 3 to 7, preferably 5 to 6, carbon atoms in the cycloalkyl part, and preferably 1 to 4, especially 1 or 2, carbon atoms in the alkyl part. The bcnzoylcycloalkylalkyl groups R preferably contain 1 to 4, especially 1 or 2, carbon atoms in each alkyl part.

The cycloalkylalkyl, benzocycloalkylalkyl and tetrahydrofuryl, tetrahydrofurfuryl and tetrahydropyranyl groups R can be substituted by one or more alkyl groups with, preferably, l to 4, especially 1 or 2, carbon atoms. The alkyl groups R substituted by one or more, preferably 1, halogen atom, especially fluorine, chlorine or bromine, or by one or more, especially one, nitrile, hydroxyl or 0x0 group, preferably contain 1 to 4, especially l or 2, carbon atoms. The carbalkoxyalkyl groups R generally contain l to 4, preferably 1 or 2, carbon atoms in the alkyl part. The cycloalkylalkoxy groups R" generally contain 3 to 7, preferably 5 or 6, carbon atoms in the cycloalkyl part and l to 4, preferably l or 2, carbon atoms in the alkyl or alkoxy compo- .nent. The cycloalkoxy groups R generally contain 3 to 7, preferably 5 or 6, carbon atoms. The alkyl or alkoxy components of the tetrahydrofurylalkoxy group, phenylalkoxy group, phenoxyalkoxy group and phenylalkyl group mentioned under R preferably contain l to 4, especially l or 2, carbon atoms. The phenylalkenyl groups R preferably contain 2 to 4 carbon atoms in the alkenyl part.

If R" represents an aromatic radical (phenyl or naphthyl or if the radicals R contain aromatic constituents (phenyl or naphthyl the aromatic structures can con tain one or more, preferably l or 2, substituents. Possible substituents are alkyl radicals with l to 4, prefcra bly l or 2, carbon atoms, alkcnyl radicals with 2 to 4 carbon atoms, alkoxy radicals with l to 4, preferably l or 2, carbon atoms, acyloxy radicals with 2 to 4, preferably 2 or 3, carbon atoms, alkylsulphonyl radicals with l to 4. preferably 1 or 2, carbon atoms, acylamino radicals with 2 to 4, preferably 2, carbon atoms, and alkylsulphonylamino radicals with l to 4, preferably l or 2, carbon atoms.

The hetero-aromatic S- or N-containing ring system R generally comprises a or 6-membered heteroaromatic ring, which can contain 1 to 3, preferably l or 2, heteroatoms, such as oxygen, sulphur and nitrogen; a benzene ring can be fused to the hetero-aromatic ring. The hetero-aromatic ring system can be substituted by one or more. preferably 1 or 2. alkyl groups with l to 4, preferably 1 or 2. carbon atoms, The fury], thienyl, isoxazolyl, pyrimidinyl, imidazolyl, pyrazolyl, indolyl. thianaphthyl, quinolyl, phenothiazinyl. thiadiazolyl and thiazolyl groups may be mentioned as examples.

Furylalkyl. thienylalkyl, indolylalkyl, furylalkyloxy and thienylalkyloxy groups R generally possess l to 4, preferably l or 2. carbon atoms in the alkyl or alkoxy component. The hetero-aromatic constituents can be substituted by one or more, preferably l or 2, alkyl groups with l to 4. preferably 1 or 2, carbon atoms.

Alkyl groups R preferably contain l to 6, especially 1 or 2, carbon atoms, and alkenyl groups R preferably contain 2 to 6 carbon atoms.

Aralkyl groups R generally contain 6 or carbon atoms in the aryl part and l to 4, preferably l or 2, carbon atoms in the alkyl part.

The cycloalkyl groups, well as the cycloalkyl constituent of the cycloalkyl-alkyl group R generally contain 3 to 7. preferably 5 or 6, ring members. The cycloalkyl-alkyl group R generally possesses l to 4, preferably l or 2, carbon atoms in the alkyl part.

The aminophenylamidines according to the invention are basic in character. They can be used as free bases or in the form of their salts, for example hydrohalides, preferably hydrochlorides, sulphates, phosphates, nitrates, acetates or naphthalenedisulphonates.

Particularly preferred compounds are those of the general formula:

R is a methyl or ethyl group;

R is a -COR group or an SO R group, {in which R is a hydrogen atom, a straightor branchedchain alkyl or alkenyl group containing up to 3 carbon atoms and optionally substituted by a trifluoromethyl or methoxy group; a cycloalkyl group with 3 to 5 carbon atoms; a furyl group; a 5- methylisoxazolyl group; a phenyl group; or an alkoxy or alkynyloxy group containing up to 4 carbon atoms and optionally substituted by a methoxy group; and R is a methyl or ethyl group;]

R is a hydrogen or chlorine atom;

R is a hydrogen atom or a methyl or ethyl group;

R is a methyl, ethyl or methoxy group;

and their physiologically tolerated salts.

Preferred salts of the new compounds are the hydrochlorides.

The invention also provides a number of processes [designated as (a), (b), (c) etc] for the production of the new aminophenylamidines and saltsv In process (a). an aniline derivative of the general formula:

is reacted with a carboxylic acid amide or thioamide of the general formula:

[in which general formula W is oxygen or sulphur and R to R, R and R" are as defined above] or with a salt or reactive derivative thereof. The reaction may be carried out in the presence of a condensation agent and [optionally] of an inert solvent. The reaction products may be isolated in the form of a salt or in the form of the free base and then converted if necessary into any other desired salt in any suitable manner.

As reactive derivatives there may be used, for example, compounds obtained by reaction of an amide or thioamide of the general formula (4) with an organic acid (for example, hydrochloric acid, boron trichloride or sulphuric acid), with an inorganic or organic acid halide (for example, phosphorus oxychloride, phosphorus pentachloride, phosgene, thionyl chloride, benzoyl bromide, p-toluenesulphonyl chloride or a mixture of phosgene/aluminium chloride or phosgene/hydrogen chloride or phosgene, or phosphorus oxychloride), with a trialkyloxonium fluoborate having 1 to 5 carbon atoms per alkyl group, with a dialkyl sulphate having I to 5 carbon atoms per alkyl group, or with an alkyl halide having l to 5 carbon atoms.

Further reactive amide derivatives that may be used are acetals and thioacetals of the general formula:

Alkyl-W [in which W, R, R and R are as defined above and Alkyl" denotes an alkyl group having up to 4 carbon atoms].

As examples of condensation agents which can be employed in process (a), there may be mentioned: inorganic acids (for example, hydrochloric acid. boron trichloride or sulphuric acid); inorganic or organic acid halides (for example, phosphorus oxychloride, phosphorus pentachloride, phosgene, thionyl chloride. bcnzoyl bromide, p-toluenesulphonyl chloride or a mixture of phosgcne/aluminium chloride or phosgene/hydrogen chloride or phosgene. phosphorus oxychloride); trialkyloxonium fluoborates. l to 5 carbon atoms per alkyl group); dialkyl sulphates l to 5 carbon atoms per alkyl group); and alkyl halides l to 5 carbon atoms).

In the case of the reaction of thioamides (general formula (4); W=sulphur), a desulphurising agent, for example, HgO, Ag O or Hg(CN) can advantageously be used additionally to these condensation agents, or without these condensation agents.

The reactants are preferably employed in the stoichiometrically required amounts.

As solvents, it is possible to use any inert organic solvents; these include aromatic. optionally halogenated, hydrocarbons, [for example, benzene, toluene and dichlorobenzenc]; optionally chlorinated aliphatic hydrocarbons [for example, methylene chloride and chloroform]; tetramethylenesulphone, and lower aliphatic alcohols; [for example, methanol and ethanol].

The reactants are preferably brought together at room temperature (about C) and can be warmed to between and lSUC, preferably 70 to 120, in order to complete the reaction.

The success of the reaction does not depend on the sequence in which the reactants are brought together. The new compounds are isolated in the usual manner.

Process (b) comprises reacting an amine of the general formula:

R! HN with an anilidc of the general formula:

B R R N -NH(R 71 H [in which general formulae W, R to R", R" and R are as defined above] or with a salt or a reactive derivative thereof.

The reaction is optionally carried out in the presence of a solvent and optionally in the presence ofa condensation agent.

Reactive anilide derivatives suitable for use in process (b) are, for example, those obtained by the reaction of an anilide of general formula (7) with an inorganic acid (such as hydrogen chloride. boron trichloride or sulphuric acid), with an inorganic or organic acid halide (such as phosphorus oxychloride, phosphorus pentachloride, phosgene, thionyl chloride, benzoyl bromide, p-toluenesulphonyl chloride or a mixture of phosgene/aluminium chloride. or phosgene/hydrogen chloride or phosgenc, phosphorus oxychloride), with a trialkyloxonium fluoborates having up to l to 5 carbon atoms in each alkyl group, with a diall-tyl sulphate having up to 5 atoms in each alkyl group or with an alkyl halide having up to 5 carbon atoms.

Other reactive anilide derivatives suitable for use in process (b) are acetals and thioacetals of the general formula:

[in which R, R, R R, R. R and W are as defined above, Alkyl denotes an alkyl group having up to 4 carbon atoms, and the two alkyl groups together can form a 5- or 6- or 7-membered ring].

Further reactive anilide derivatives suitable for use in process (b) are iminoethcrs of the general formula:

[in which general formulae W, R to R", R and R are as defined above].

The progress of the reaction can be followed from the accompanying evolution of CO; or COS.

Process (d) comprises heating a compound of the general formula:

3,9ll,OlO

with an amide or thioamide of the general formula:

[in which general formulae R to R, R", R and W are as defined above].

In the processes c) and (d), the reactants are preferably reacted in molar ratios.

The reactions are expediently carried out at temperatures between 80 and 200C, preferably between I l and I8UC, optionally in the presence of an inerg organic solvent.

As examples of such solvents suitable for use in process (c) or (d) there may be mentioned benzene, toluene and dichlorobenzene.

Process (e) is applicable to those aminophcnylamidines of the invention in which R and R are alkyl or alltenyl groups, and comprises reacting a phenylamidine of the general formula:

with an alkylating agent of the general formula:

[in which general formulae R, R, R, R and R are as defined above, R'" is a straightor branched-chain alkyl or alkenyl group, and B is a reactive ester group or a halogen atom].

Preferred halogen atoms B are chlorine, bromine and iodine. Prefercd reactive ester groups are arylsulphonyloxy and alkylsulphonyloxy groups, for example, methanesulphonyloxy and toluenesulphonyloxy groups.

The compounds of the general formula 13) can, for example. be obtained in a known manner by the reaction of an aniline derivative of general formula (3) with a nitrile of the general formula:

R C N (15) [in which R is as defined above], optionally in the presence of a condensation agent [for example, aluminium chloride].

The reactants in process (e) are preferably employed in molar amounts. The reaction takes place at temperatures between 0 and 120C, and is preferably carried out at 20 to C, in the presence of an inert organic solvent.

Ethers, [for example, diethyl ether or tetrahydrofurane] and alkylnitriles [for example, acetonitrile] are, for example, suitable as solvents. It can, at times, also be desirable to add an acid-binding agent, for example, an alkali metal carbonate or an alkaline earth metal carbonate, preferably sodium or potassium carbonate.

Finally, process (f) comprises reacting an aminophcnylamidine of the general formula:

with an acylating or sulphonylating agent of the general formula:

[in which general formulae R, R, R", R" and R" are as defined above, Z is a group COR or SO R in which R" and R are as defined above, and Y is a reactive acid group or a halogen atom] optionally in the presence of a solvent and optionally in the presence of an acid-binding agent.

Halogen atoms Y are preferably chlorine and bromine atoms. When 2 is a COR group, Y is a O- CO-R" or OR' group [in which R" and R"' are as defined above for R and can be the same or different to R in the acylating or sulphonylating agent of general formula (17)].

If 2 is an SO R group, Y is a halogen atom.

As the alkylating or sulphonylating agent Y-Z, there may especially be mentioned: lower alkylpyrocarbonic acid esters with l to 4 carbon atoms in the alkyl part; lower chloroformic acid alkyl esters with, preferably, 1 to 4 carbon atoms in the alkyl component; lower alkylcarboxylic acid chlorides and bromides with, preferably, l to 4 carbon atoms in the alkyl group; formic acid alkyl esters with l to 4 carbon atoms in the ester part; methanesulphonic acid chloride; benzoyl chloride and acetic anhydride; or mixed anhydrides, such as formicacetic anhydride.

In process (f), the reactants are preferably brought together in molar amounts.

The reaction temperatures are expediently 0 to l20C, preferably 20 to C.

As solvents, it is possible to employ any solventv that is inert during this reaction. Lower aliphatic alcohols [for example, methanol or ethanol], aromatic hydrocarbons [for example, benzene and toluene], petroleum ether, chlorinated hydrocarbons [for example, chloroform and methylene chloride], as well as tetramethylenesulphone, may be mentioned as examples.

The aminophcnylamidines lo) can for example be obtained from the nitrophenylamidines and/or their salts, of the general formula:

aniline; carhallyloxyamino-2-chloro-aniline; 4- carbethoxyamino-Ii-chloro-S-methyl-aniline; 4- carbethoxy-amino-S .S-dimethylaniline; 4-( N- carbethoxy-N-methyl-amino )-anil ine; 4-carbethoxyamino 3-hromoaniline; 4-earbethoxyaminotrill uoromethylaniline; 2t5-dichloro-4-acetaminoaniline; 2.5-dichloro-4-carbethoxyamino-aniline; 3,5-

dichloro-4-carbethoxyanilinc; 2-chloro-4-carbethoxy- S-methylaniline; 5-chloro-4-carbethoxy-Z-methylaniline and 2.4-dimethyl-S-carbethoxyamino-aniline; N-(4-nitrophenyl N'. N'-dimethyl-acetamidine; N-(4- nitrophenyl )-N .N '-diethyl-acctamidine; N-( 4- nitrophenyl )-N .N '-dimethylpropionamidine; N-( 4- nitrophenyl)-N.N'-diethylpropionamidine and N-(4- nitrophenyl )-N'-ethyl-N-methyl-aeetamidine.

The salts of the aminophenylamidines according to the invention can be obtained from the free bases in the usual manner.

The production of the new compounds by processes according to the invention is illustrated in the Examples which follow:

All temperatures are given in C.

EXAMPLE I T a CH1:

u qooc- NH- 4-Carbethoxyamino-aniline and 46.6 g of N,N- dimethyl-acetamidc are dissolved in 1000 ml of toluene. 79.5 g of phosphorus oxychloride are added dropwise thereto at and the mixture is stirred for 90 minutes at 20 and heated for 4 hours under reflux After decanting off the toluene, the residue is taken up in a mixture of water and chloroform, sodium hydroxide solution is added whilst cooling, inorganic products are filterd off. and the organic phase is separated off.

After evaporating the organic phase. 101 g of crude N- (4-carhethoxyaminophenyl )-N .N -dimethylacetamidine are obtained; this is recrystallised from ethyl acetate. Melting point l30-l 31, yield 84 g. The hydrochloride is obtained by dissolving the compound in ether and adding a solution of hydrochloric acid in ether. and is recrystallised from a mixture of ethyl acetate and alcohol. Melting point 222 (decomposition). The same compound is also obtained if phosgene or ptoluenesulphonyl chloride are used as condensation agents.

The following compounds are prepared by proceeding analogously:

N-( 4-carbomethoxyaminophenyl )-N ,N

dimethylacetamidine, melting point l37l 39;

N-( 4-earbethoxyaminophenyl )-N .N'-dimethylpropionamidine, melting point 1 14] 15;

N-( 4-carbethoxyaminophenyl )-N ,N '-dimethylbutyramidine;

N-( 4-carbethoxyaminophenyl )-N',N '-dimethylisobutyramidine;

N-(4-carbethoxyaminophenyl)-N',N'-dimethylpivalylamidine;

N-(4-carbethoxyaminophenyl)-N',N-dimethylvaleramidine;

N-( 4-earbcthoxyaminophcnyl )-N ,N'-dimethylacrylamidine;

N-( 4-carbethoxyaminophenyl )-N ,N-dimethylcrotylamidine;

N-( 4-earbethoxyaminophenyl )-N ',N '-dimethyl-B,B-

dimethyl-acrylamidine;

N-( 4-carbethoxyaminophenyl )-N ',N 'dimethyl-amethaerylamidine;

N-( 4-carbethoxyaminophenyl)-N ,hV-dimethylmethoxyacetamidine;

N-( 4-carbethoxyaminophenyl )-N '.N'-dimethylethoxyacetamidine;

N-( 4-carbethoxyaminophenyl )-N ',N -dimethylcyclopropyl-earboxamidine;

N 4-carbethoxyaminophenyl )-N',N

dimethyleyclobutylcarboxamidine;

N-( 4-carbethoxyaminophenyl )-N '.N'-dimethylcyclopentylcarboxamidine;

N-( 4-earbethoxyaminophenyl )-N',N'-dimethylcyclohexylcarboxamidine;

N-( 4-carbethoxyaminophenyl )-N ',N'-

diethylacetamidine; melting point 8890;

N-( 4-earbethoxyaminophenyl )-N '-ethyl-N-methylaeetamidine, melting point lO5-l07; hydrochloride, melting point l196;

N-( 4-carbethoxyaminophenyl )-N '-methyl-N propyl-acetamidine;

N-( 4-carbethoxyaminophenyl )-N '-ethyl-N'-propylaeetamidine;

N-( 4-carbethoxyaminophenyl )-N '-methyl-N-isopropyl-aeetamidine;

N-( 4-carbcthoxyaminophenyl )-N '-allyl-N-methylacetamidine;

N-( 4-carbcthoxyaminophenyl )-N '-erotyl-N'-methylacetamidine',

N-( 4-carbethoxyaminophenyl )-Nmethallyl-N methyl-acetamidine;

N-( 4-carbethoxyaminophenyl )-N'-methyl-N B- methyl-vinyl )-acetamidine;

N-( 4-carbethoxyaminophenyl )-N -methyl-N'( Bfidimcthyl-vinyl )-aeetamidine;

EXAMPLE I4 50 ml of dimethylacetamide and g of P- acetaminophenylisocyanate are heated under reflux until the evolution of CO has ceased. The reaction product is distilled in vacuo, and 7.5 g of N-(4- acetaminophenyl)-N',N'-dimethylacetamidine, boiling point ,l8()2()(), melting point l3ll34, are obtained.

The same compound is also obtained by heating 4-acetamino-phenylcarbamine acid chloride and with dimethyl-acetamide or dimethylthioacetamide.

EXAMPLE I5 98 g of 4-acetaminophenyl-acetiminoethyl-ethcr in a solution of 26 g of dimethylamine in l()() ml of ethanol are heated for 2 days to 28 and then for 6 hours in a sealed tube to 12()l After evaporation and distillation, 57 g of N-(4-acetaminophenyl)-N',N'- dimethylacetamidinc. melting point 13 ll 34, are obtained. Corrcspondingly, reaction of 4- acetiminophcnyl-acetiminoethyl-ether with ammonia yields N( 4-aeetaminophenyl)-acetamidine. The same compound is also produced by reaction of 4- aminoaectanilide with acetiminoethyl-ethcr.

EXAMPLE l6 [Production of a starting material for use in a process of the invention 140 g of p-amino-acetanilide and 36 g of acetonitrile in 400 ml of carbon disulphide are treated with 144 g of aluminum chloride over the course of l hour. The solvent is then distilled off, and the reaction mixture is heated for 4 hours to l 1 Thereafter it is poured onto a mixture of ice and water. the whole is filtered, the filtrate is rendered alkaline with saturated potassium carbonate solution. and the oil which has separated out is taken up in ether. After evaporating off the solvent, 33 g of N-(4-acetaminophenyl )-acetamidine are obtained. Boiling point 173 176".

EXAMPLE 17 l l g of sodium carbonate are added to a solution of 38.2 g of N-(4-acetaminophenyl)-acetamidine [as produced in Example 16] in 200 ml of tetrahydrofurane, and 57 g of methyl iodide are added dropwise. The mixture is heated overnight under reflux. inorganic constituents which have separated out are filtered off, the filtrate is concentrated in vacuo. and the residue is taken up in water and rendered alkaline with sodium hydroxide solution. The separated base is taken up in a mixture of ether/chloroform, which is evaporated, and is distilled. After recrystallisation from ethyl acetate. 17.8 g of N-( 4-acetaminophenyl )-N ',N '-dimethylacetamidine of melting point l3l-l34 are obtained.

The following are obtained by analogous processes:

N-( 4-acetaminophenyl )-N '-allyl-acetamidine;

N-( 4-acetaminophenyl )-N -methallyl-acctamidine;

N( 4-acetaminophenyl )-N '-crotylacctamidine;

N-(4-propionylaminophcnyl)-N-allyl-acetamidine;

N-( 4-propionylaminophenyl)-N'-metha1lylacctamidinc;

N-( 4-carbethoxyaminophenyl J-N -allylacetamidine;

N-( 4-carbethoxyaminophenyl )-N '-crotylacetamidine;

N-( 4-methanesulphonylaminophenyl )-N '-allylacetamidinc:

N-(carbethoxyaminophenyl )-N'.N'-diall lacetamidine; N-( 4-acetaminophenyl )-N,N -diallyl-acetamidine; N-( 4-propionaminophenyl )-N',N'-diallyl- 5 acetamidine;

N-( 4-methylsulphonylaminophenyl )-N'.N'-diallylacetamidine; and N-( 4acetaminophenyl )-N ',N'-dicrotyl-acetamidine.

EXAMPLE l8 Following the method described in Example l7, alkylation of N-(4-acetaminophenyl)-N'- methylacetamidine with allyl chloride in the presence of potassium carbonate yields N-(4-acetaminophenyl N-allyl-N'-methyl-acetamidine.

The following are obtained by proceeding analogously:

N-( 4-acetaminophenyl )-N-methyl-N -crotylacetamidine;

30 N-( 4-acetaminophenyl )-N '-methyl-N'-methallylacetamidine; N-( 4-acetaminophenyl )-N '-methyl-N'-propinylacetamidine; N-( 4-acetaminophenyl )-N '-methyl-N'-butinyl-( 2 35 acetamidine;

N-( 4-propionaminophenyl )-N '-methyl-N -allylacetamidine; N-( 4-propionaminophenyl )-N'-methyl-N '-crotylacetamidine; 30

N-( 4-propionaminophenyl )-N-ethyl-N-allylacetamidine;

N-( 4-carbethoxyaminophenyl )-N -methyl-N '-allylacetamidinc;

N-( 4-carbcthoxyaminophenyl )-N -methyl-N-butinyll l H. a. 0 l

(O-NH- N -N (29) S Following the method described in Example 9, 17.7

g of N-(4-aminophenyl)-N',N'-dimethylaeetamidine and 15.7 g of Z-furanecarboxylic acid chloride in ethanol yield 27.7 g of N-[4-(2-furylcarbonyl)- aminophenyll-N',N'-dimethyl-acetamidine hydrochloride, melting point 27()272.

60 The following are obtained by analogous processes:

N-{4-( S-methylisoxazolylcarbonyl-[3 aminophenyl ]-N',N-dimethyl-acetamidine. hydrochloride, melting point 3()8-309, decomposition; N-[ 4-( 2-pyridylcarbonyl )-aminophenyl ]-N',N

dimethyl-acetamidine; N-[ 4( 3-pyridylcarbonyl l-aminophenyl ]-N'.N'-

dimethyl-acetamidine;

N-l4-(4-pyridylcarbonyl)-aminophenyl]-N',N'-

dimethyl-acetamidine;

N-[ 4-( Z-thienylcarbonyl )-aminophenyl ]-N'.N

dimethyl-acetamidine;

N- 4-( Z-furfurylcarbonyl )-aminophenyl ]-N'.N-

dimethyl-acetamidine;

N-[ 4-( Z-indolylcarbonyl )-aminophenyl ]-N '.N'-

dimcthyl-acetamidinc;

N-[4-( 2thianaphthylcarbonyl )-aminophenyl N .N '-dimcthyl-acetamidine;

N-[4-( 3-indolylacetyl )-aminophcnyl ]-N'.N'-

dimethyl-acetamidine;

N-[4-( 3-quinolylcarbonyl )-aminophenyl ]-N'.N

dimethyl-acetamidine;

INH 4-( Z-phenothiazinylcarbonyl J-aminophenyl N.N'-dimethyl-acetamidine;

dimethyl-acetamidine;

N-[4-( 3-pyrazolylcarbony1)-aminophenyl]-N.N-

dimethyl-acetamidine;

N-[ 4-( 4-methyl-3-pyrazolylcarbonyl )-aminophenyl N'.N'-dimethyl-aeetamidine;

N-[ 4-( Z-imidazolylcarbonyl )-aminophenyl ]-N',N'-

dimethyl-acetamidine;

N-l 4-pyrazinylcarbonyl-aminophenyl ]-N,N'-

dimethyl-acetamidine;

N-l 4-( 4-pyrimidinylearbonyl )aminophenyl ]-N,N'-

dimethyl-acctamidine; and

dimethyl-acetamidine.

As already mentioned, the new aminophenylamidines and salts are suitable for combating parasites. especially helminths.

lt is distinctly surprising and unforeseeable that a high anthclmintic activity should arise as a result of the introduction of an aeylamino or of a sulphonylamino group into the phenyl nucleus of the N- phenylacetamidines. Furthermore. the new compounds have a substantially better action than other known anthelmintics having the same type of action, such as. for example. bephenium hydroxynaphthoates, phenylene- 1 .4-diisothiocyanatc. perchloroethylene. thiabendazole and parbendazole. Particular attention is drawn to the fact that excellent results are achieved with a single dose.

The provision by the invention of the new compounds available extends substantially the range of available medicines.

In particular, the compounds manufactured according to the invention for example display a surprisingly good and broad action against the following helminths (nematodes and cestodes):

l. Nl-IMATODES family of the Rhabditidae;

5. Tuxocaru canis, Toxascuris Ieonina and Ascaris .ruum larvae (coilworms) from the family of the Ascarididae.

6. Aspiculuris tetrupleru (maggot worms) from the family of the Oxyuridae;

7. Heterakis spumosa from the family of the Heterakidue.

11. CESTODES l. H \-men0lepis mum and Hymenolepis microsroma (tapeworms) from the super-family of the Taenioidea.

The action was tested in animal experiments, by oral and parenteral administration to test animals severely infected with parasites. The doses used were tolerated very well by the test animals. Even at 10 to 100 times the therapeutically necessary dose, the test animals survived the treatments.

The unexpected superiority of the compounds according to the invention over known compounds, as well the excellent action against a multiplicity of parasites, is shown by the Examples A to G (Tables 1-7).

EXAMPLE A Hookworm test/dog Dogs experimentally infected with Am'ylostome cana mun were treated after the end of the pre-patent period of the parasites.

The amount of active compound was administered orally as the pure active compound or as a 10% strength solution in lactic acid, in gelatine capsules.

The degree of action was determined by counting the worms expelled after the treatment and the worms remaining in the test animal. after dissection. and calculating the percentage of worms expelled.

The active compounds tested, doses used and action are summarised in Table 1 below.

Table l Hookworm test/dog Table l -Continued Hookworm lest/dog Active compounds Dose Action Hookworm test/dog Table 2 Hookwurm test/dog Active compounds Dose Action rug/kg in i I N C- C 'NH e '\'=('-N [19) HI )2 5 9:

mg/kg in '7! ll) K2 Table 2 -Continued Hookworm test/dog Hookworm test/dog Dogs experimentally infected with Ancylostoma caninum were treated after the end of the pre-patent period of the parasites.

The amount of active compound was administered subcutaneously as a l7c strength solution in distilled water.

The degree of action was determined by counting the worms expelled after the treatment and the worms remaining in the test animal, after dissection, and ealcu- EXAMPLE E lating the percentage of worms expelled.

The active compound tested, dose used and action are summarised in Table 3 below. Sheep experimentally infected with Hucnmm'hm mn- Stomach and intestine worm test/sheep Table 3 Hookworrn test/dog Acthe compound Dose Action mg/kg in H ,C,OOC-NH- N --N HCl 5 99 EXAMPLE D mm and Hit-hostmngylus cululn'ljbrmis were treated after the end of the pre-patent period of the parasites. The amount of active compound was administered orally as pure active compound, in gelatine capsules.

The degree of action is determined by quantitatively counting the worm eggs excreted with the faeces before and after treatment.

Hookworm test/sheep 10 Sheep experimentally infected with Bmmsmmum Irigmmcep/iu/um were treated after the end of the prepatent period of the parasites.

The amount of active compound was administered orally as pure active compound in gelatine capsules.

The degree of action is determined by counting the worms expelled after the treatment and the worms remaining in the test animals, after dissection, and calculating the percentage of worms expelled.

The active compounds tested. doses used and action The active compound tested and the minimum effecare summarised in Table 4 below. tive dose is shown in Table 5.

Complete cessation of the excretion of eggs after treatment means that the worms have been expelled or so damaged that they can no longer produce eggs (effective dose).

Table 4 Hookworm test/sheep Active compound Dose Action mg/kg in /r H1 H1 l 1.0 H -,C OOCNH N N (l9) 15 98 5.0 100 H,-, CH H C OOCNH N=C'-N .HCI l.() 92 (50) 5.0 9:;

H COOCNH N -N I0 I00 Table 5 Stomach and intestine worm test/sheep Minimum effective Active compound Parasite dose mg/kg Hucmonchus l 0 a CH contortus H,,C OOC- NH a Trichostr.

colubriformis 25 Table 6 Large-intestine worm test/sheep Active compounds Dose Action mykg in X CH 11) 65 5.0 100 H -C:OOCNH N=C- HM) H10 l T H C- -OOCNH N=( .HCl L0 76 EXAMPLE F EXAMPLE G Large-intestine worm test/sheep C oilworm test/dog Dogs naturally infected with Tuxucuru cams and 10xast'clrix Iemu'na were treated orally.

The amount of active compound was administered 0- rally as pure active compound or as a 10% strength solution in lactic acid. in gelatinc capsules. The degree of action is determined by counting the worms expelled after the treatment and the worms remaining in the test animals. after dissection, and calculating the percentage of worms expelled.

The active compounds tested. doses used and action are summarised In Table 7 below.

Table 7 Coilworm test/dog Table 7 -Continued (oilworm test/dog (27) in, ':Ha o

HN N N .HCI Toxocara 100 H I I CH3 N l o CO-HN- -N=CN\ HCl (46) Toxocara 10 100 In general it has proved advantageous to administer amounts of about 0. l to about 50 mg of the new compounds per kg of body weight per day in order to achieve effective results.

Nevertheless, it may at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the test animal or of the nature of the method of administration, but also because of the variety of animal and its individual behaviour towards the medicament or because of the nature of the formulation of the latter and the point in time, or interval, at which it is administered. Thus, it may in some cases suffice to use less than the abovementioned minimum amount, whilst in other cases the upper limit mentioned must be exceeded. Where major amounts are administered, it may be advisable to divide these into several individual administrations over the course of a day. The same dosage range is envisaged for administration in human medicine and in veterinary medicine. The general sense of the other comments made above also applies.

As stated above, the invention relates to the pharmaceutical use, including the veterinerary use, of the new aminophenylamidines and their non-toxic salts.

Accordingly, the present invention provides a pharmaceutical composition containing as an active ingredient at least one of the new aminophenylamidines of the general formula l given above, or a non-toxic salt thereof, in admixture with a pharmaceutically acceptable solid or liquid diluent or carrier as hereinafter dcfined.

1n the present specification the expression pharmaceutically acceptable diluent or carrier" means a nontoxic substance that when mixed with the active ingrepharmaceutically necessary ingredients such as salts in correct quantities to render the composition isotonic, buffers, surfactants, colouring and flavouring agents, and preservatives. Examples of suitable solid and liquid diluents and carriers are the following: water containing buffering agents and/or rendered isotonic by the addition of glucose or salts; non-toxic organic solvents; such as paraffins, (for example petroleum fractions); vegetable oils (for example groundnut/sesame oil); alcohols, (for example ethyl alcohol or glycerol); glycols (for example propylene glycol or polyethylene glycol);

natural ground rock (for example kaolins, aluminas, talc or chalk); synthetic rock powders (for example highly disperse silica or silicates); and sugars (for example unrefined sugar, lactose and glucose).

Examples of pharmaceutical compositions according to the invention are ointments, pastes, creams, sprays, lotions, aqueous suspensions, elixirs, syrups, granules and'powders, either free-flowing or compressed into tablets.

The compounds and pharmaceutically acceptable salts of the present invention may be administered perorally.

One group of preferred pharmaceutical compositions of the invention are therefore those adapted for oral administration. The diluents and carriers used are preferably therefore those that adapt the active ingredient or ingredients for oral administration. Examples of such diluents and carriers are solid vehicles. excipients and lubricants such as glucose. lactose and sucrose. corn and potato starch. sodium carboxymethyl cellulose. ethyl cellulose and cellulose acetate. powdered gun tragacanth. gelatin. alginic acid. agar. stearic acid. sodium. calcium and magnesium stearates. sodium lauryl sulphate. polyvinyl-pyrollidone. sodium citrate. calcium carbonate. and dicalcium phosphate.

The pharmaceutical compositions of the invention may also contain other non-toxic adjuvants and modifiers such as dyes. surfactants [for example. emulsifiers. such as nonionic and anionic emulsifiers (for example polyoxycthylcnefatty acid esters. polyoxyethylene-fatty alcohol ethers. alkylsulphonates and arylsulphonates). and dispersing agents (for example lignin. sulphite waste lyes. methylcellulose. starch and polyvinylpyrrolidonel]. perfumes. flavouring agents, preservatives and biocidcs.

The compounds and pharmaceutically acceptable salts of the invention may also be administered parenterally. in particular. subcutaneously. A group of preferred pharmaceutical compositions of the invention are therefore those adapted for parenteral injection. The diluents and carriers used here are therefore preferably those that adapt the active ingredient for parenteral administration. Examples of such diluents and carriers are solvents and suspending diluents such as water and water-miscible organic solvents. in particular sesame oil. groundnut oil. aqueous propylene glycol. and N.N'-dimethyl formamide. Examples of pharmaceutical compositions of the invention are sterile isotonic saline aqueous solutions of the active ingredient. which may be buffered with a pharmaceutically acceptable buffer and are preferably pyrogen-free.

The pharmaceutical compositions of the invention preferably contain ().l to 90 wt.7r of a new aminophenylamidine of the invention or a non-toxic salt thereof.

The present invention also provides medicaments in dosage unit form as hereinafter defined comprising as an active ingredient at least one aminophenylamidine of general formula l given above or a non-toxic salt thereof. either alone or in admixture with a pharmaceutically acceptable solid or liquid diluent or carrier. In this case the dilluent or carrier is preferably as defined above but can also be water or another common solvent.

The expression "medicament in dosage unit form as used in the present specification means a medicament in the form ofdiscrete portions each containing a unit dose or a multiple or sub-multiple of a unit dose of the active ingredient(s); for example, one. two. three or four unit doses or a half, a third or a quarter of a unit dose. A unit dose" is the amount of the active ingredient( s) to be administered on one occasion and will usually be a daily dose. or for example a half. a third. or a quarter of a daily dose depending on whether the medicament is to be administered once or. for example. twice. three times. or four times a day.

The discrete portions constituting the medicament in dosage unit form can include a protective envelope. The active ingredient can be undiluted and contained in such an envelope. or can be mixed with a pharmaceutically acceptable solid or liquid diluent or carrier as defined above. Such portions can for example be in monolithic coherent form. such as tablets. lozenges. pills. suppositories. or dragees; in wrapped or concealed form. the active ingredients being within a protective envelope. such as wrapped powders. cachets. sachets. capsules. or ampoules; or in the form ofa sterile solution suitable for parenteral injection. such as ampoules of buffered. isotonic. sterile, pyrogen-free aqueous solution; or in any other form known in the art.

As stated above. it is preferred to administer the new aminophenylamidines of general formula l or their salts perorally. Preferred medicaments in dosage unit form according to the invention are therefore those adapted for oral administration. such as tablets. pills. dragees. capsules. and cachets, as well as wrapped powders containing the active ingredient in powdered form with a powdered diluent or carrier for suspension in water before being taken.

As stated above the new aminophenylcycloamidines can also be administered parenterally. Preferred medicaments in dosage unit form according to the invention are therefore those adapted for parenteral injection. such as ampoules containing a measured quantity of a sterile isotonic saline injectable aqueous solution of the new active ingredient. which may be buffered with a pharmaceutically acceptable buffer and are preferably free of pyrogens.

The preferred unit dose for administration in human medicine of the medicaments of the invention is 5-4500 mg. more preferably 50-2250 mg of active ingredient.

The invention further provides a method of combating parasitic infection in an animal which comprises administering to the animal (preferably parenterally or perorally) an aminophenylamidine of general formula (1 l or a non-toxic salt thereof. or a pharmaceutical composition according to the invention, or a medicament in dosage unit form according to the invention.

What we claim is:

l. A compound selected from the group consisting of an aminophenylamidine and the physiologically acceptable acid addition salts thereof. said aminophenylamidine having the formula wherein R is alkyl of 1 to 5 carbon atoms. alkenyl of 2 to 5 carbon atoms or cycloalkyl of 3 to 7 carbon atoms;

R is hydrogen, chloro. fluoro. bromo, cyano. trifluoromethyl. nitro. alkyl of up to 4 carbon atoms. alkoxy of up to 4 carbon atoms and alkenyl of up to 4 carbon atoms;

R is an aliphatic substituent of up to 4 carbon atoms selected from the group consisting of alkyl, alkenyl. alkynyl and alkoxy;

R is an alkyl of l to 3 carbon atoms or alkoxy of l to 3 carbon atoms; and

R is hydrogen or an aliphatic substituent of up to 6 carbon atoms selected from the group consisting of alkyl. alkcnyl. alkynyl and alkoxyalkyl. said aliphatic substituent being unsubstituted or substituted by fluoro. chloro. hromo hydroxy or cyuno. 5. The compound according to claim I which is 2. A compound according to claim I wherein R is methyl or ethyl;

R is hydrogen or chloro'. T R is alkyl of l to 3 carbon atoms or ulkoxy of l to 5 ('H() (H ,.A('O .NH M l 3 carbon atoms;

R is alkyl of l to 3 carbon atoms; and R is alkyl of up to 3 carbon atoms. unsubstituted or substitutcd by fluoro or mclhox or ulkcnyl of up to 3 carbon atomsv m 3. The compound according to claim I which is N-(4- 6. The compound according to claim I which is hydrochloride salt thereof 4. The compound according to claim 2 which is N-( 4- fiirmylaminophcnyl J-N .N'-dimclhylucctaimidinc or the hydrochloride salt thereof. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF AN AMINOPHENYLAMIE AND THE PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, SAID AMINOPHENYLAMINE HAVING THE FORMULA
 2. A compound according to claim 1 wherein R is methyl or ethyl; R3 is hydrogen or chloro; R4 is alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; R5 is alkyl of 1 to 3 carbon atoms; and R6 is alkyl of up to 3 carbon atoms, unsubstituted or substituted by fluoro or methoxy, or alkenyl of up to 3 carbon atoms.
 3. The compound according to claim 1 which is N-(4-acetylaminophenyl)-N'',N''-dimethylacetamidine or the hydrochloride salt thereof.
 4. The compound according to claim 2 which is N-(4-formylaminophenyl)-N'',N''-dimethylacetamidine or the hydrochloride salt thereof.
 5. The compound according to claim 1 which is
 6. The compound according to claim 1 which is 